Mutations Predict Colorectal Tx Response

Action Points

Note that this retrospective analysis of a randomized trial demonstrated that, in patients with metastatic colorectal cancer, the presence of a RAS mutation predicts harm from the addition of panitumumab to traditional FOLFOX4 therapy.

Be aware that routine testing for RAS mutations is not yet available.

Among patients with metastatic colorectal cancer, only those who had no activating RAS mutations benefited from treatment targeting the epidermal growth factor receptor (EGFR) with panitumumab (Vectibix), an retrospective analysis of findings from a large prospective study found.

Patients without any RAS mutations in the EGFR signaling pathway had significantly longer progression-free survival when given panitumumab plus conventional oxaliplatin-based chemotherapy (10.1 months versus 7.9 months, P=0.004), according to Jean-Yves Douillard, MD, PhD, of the Institut de Cancerologie de l'Ouest Rene Gauducheau in Nantes, France, and colleagues.

In addition, that group of patients had greater overall survival (26 months versus 20.2 months, P=0.04), the researchers reported in the Sept. 12 issue of the New England Journal of Medicine.

"Although KRAS testing has facilitated the selection of patients who are most likely to have a response to anti-EGFR therapy, a substantial fraction of patients do not benefit from treatment. It is hoped that further refinement of tumor-specific genetic markers will allow more accurate selection of patients," the researchers wrote.

An additional study of biomarkers suggested that a number of related genes might also predict a lack of response, so Douillard's team conducted further analyses on the PRIME data, focusing on mutations other than KRAS in exon 2.

These included mutations in KRAS in exons 3 and 4, mutations in NRAS in exons 2, 3, and 4, and BRAF in exon 15.

In this analysis, among 108 patients without KRAS mutations in exon 2 but with other RAS mutations, median progression-free survival was 7.3 months in the panitumumab plus FOLFOX4 group and 8 months in the FOLFOX4-only group, with a hazard ratio of 1.28 (95% CI 0.79-2.07, P=0.33).

In contrast, for the 512 without any RAS mutations the hazard ratio for progression or death when treated with the combination was 0.72 (95% CI 0.58-0.90, P=0.004).

An interaction test between groups with no RAS mutations and those who had RAS mutations without KRAS mutations in exon 2 showed a significant interaction for progression-free survival (P=0.04), although the test wasn't significant for overall survival.

That test included patients in PRIME's initial analysis, done at the original data cutoff point in August 2009, when 54% of patients had died.

But an updated interaction test, using data collected through January 2013 when 82% had died, also was significant for survival (P=0.01).

"These results indicate that treatment effects differed between the subgroups of patients without RAS mutations and those without KRAS mutations in exon 2 but with other RAS mutations, suggesting that RAS mutations, in addition to KRAS mutations in exon 2, were negative predictive factors," the researchers observed.

They also looked at the effects of BRAF mutations, and found shorter progression-free survival in both treatment groups, suggesting that this too was a negative predictor.

There were no new safety signals in this analysis.

In an accompanying editorial, Jordan Berlin, MD, of Vanderbilt University in Nashville, noted that these findings "pose an intriguing challenge to medical oncologists," who now have to decide on whether to expand genetic tumor testing, given that an additional prospective study is unlikely to be done.

"Although the study presented here is not definitive enough to require a change from the limited KRAS exon 2 testing currently performed to a broader assessment of RAS status, presuming other analyses support these results, it would be difficult to justify taking a long time to change practices," Berlin observed.

Daniel Catenacci, MD, of the University of Chicago, who wasn't involved in the study, agreed with Berlin. "Being the first of its kind, this study was very intriguing. If other studies now in motion show similar findings, I think that testing for these other mutations will become standard. But a little more data is still needed," he told MedPage Today in an interview.

The study also reinforced the value of preserving tissue specimens from patients participating in clinical trials so that genetic analyses can be performed as knowledge advances, according to Berlin.

"Doing so will mean that drugs that initially appeared to be minimally effective may be administered to the right patients for maximal benefit," Berlin wrote.

Limitations of the study included its retrospective, exploratory design.

The study was supported by Amgen, the Royal Marsden Hospital, the Institute of Cancer Research, National Institute for Health Research, Biomedical Research Center, and Oncologia Ca' Granda Onlus Fondazione.

Many of the investigators disclosed financial and advisory ties with Amgen, and to numerous other companies such as Roche, Merck, Pfizer, Janssen, and Sanofi-Aventis.

Six of the authors were employees of Amgen and held stock in the company.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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